School of Life Sciences, Jilin University, Changchun, Jilin, China.
PLoS Genet. 2013 Nov;9(11):e1003940. doi: 10.1371/journal.pgen.1003940. Epub 2013 Nov 14.
hMOF (MYST1), a histone acetyltransferase (HAT), forms at least two distinct multiprotein complexes in human cells. The male specific lethal (MSL) HAT complex plays a key role in dosage compensation in Drosophila and is responsible for histone H4K16ac in vivo. We and others previously described a second hMOF-containing HAT complex, the non-specific lethal (NSL) HAT complex. The NSL complex has a broader substrate specificity, can acetylate H4 on K16, K5, and K8. The WD (tryptophan-aspartate) repeat domain 5 (WDR5) and host cell factor 1 (HCF1) are shared among members of the MLL/SET (mixed-lineage leukemia/set-domain containing) family of histone H3K4 methyltransferase complexes. The presence of these shared subunits raises the possibility that there are functional links between these complexes and the histone modifications they catalyze; however, the degree to which NSL and MLL/SET influence one another's activities remains unclear. Here, we present evidence from biochemical assays and knockdown/overexpression approaches arguing that the NSL HAT promotes histone H3K4me2 by MLL/SET complexes by an acetylation-dependent mechanism. In genomic experiments, we identified a set of genes including ANKRD2, that are affected by knockdown of both NSL and MLL/SET subunits, suggested they are co-regulated by NSL and MLL/SET complexes. In ChIP assays, we observe that depletion of the NSL subunits hMOF or NSL1 resulted in a significant reduction of both H4K16ac and H3K4me2 in the vicinity of the ANKRD2 transcriptional start site proximal region. However, depletion of RbBP5 (a core component of MLL/SET complexes) only reduced H3K4me2 marks, but not H4K16ac in the same region of ANKRD2, consistent with the idea that NSL acts upstream of MLL/SET to regulate H3K4me2 at certain promoters, suggesting coordination between NSL and MLL/SET complexes is involved in transcriptional regulation of certain genes. Taken together, our results suggest a crosstalk between the NSL and MLL/SET complexes in cells.
hMOF（MYST1）是一种组蛋白乙酰转移酶（HAT），在人类细胞中至少形成两种不同的多蛋白复合物。雄性特异性致死（MSL）HAT 复合物在果蝇中的剂量补偿中起着关键作用，负责体内的组蛋白 H4K16ac。我们和其他人之前描述了第二种含有 hMOF 的 HAT 复合物，即非特异性致死（NSL）HAT 复合物。NSL 复合物具有更广泛的底物特异性，可在 K16、K5 和 K8 上乙酰化 H4。WD（色氨酸-天冬氨酸）重复结构域 5（WDR5）和宿主细胞因子 1（HCF1）是混合谱系白血病/SET （混合谱系白血病/SET 结构域包含）家族的组蛋白 H3K4 甲基转移酶复合物成员之间共享的。这些共同亚基的存在提出了这样一种可能性，即这些复合物及其催化的组蛋白修饰之间存在功能联系；然而，NSL 和 MLL/SET 相互影响的程度尚不清楚。在这里，我们通过生化测定和敲低/过表达方法提供了证据，证明 NSL HAT 通过一种依赖于乙酰化的机制促进 MLL/SET 复合物的组蛋白 H3K4me2。在基因组实验中，我们鉴定了一组包括 ANKRD2 在内的基因，这些基因受到 NSL 和 MLL/SET 亚基敲低的影响，表明它们受到 NSL 和 MLL/SET 复合物的共同调控。在 ChIP 测定中，我们观察到 NSL 亚基 hMOF 或 NSL1 的耗竭导致 ANKRD2 转录起始位点近端区域附近的 H4K16ac 和 H3K4me2 的显著减少。然而，RbBP5（MLL/SET 复合物的核心组成部分）的耗竭仅降低了 ANKRD2 同一区域的 H3K4me2 标记，但不降低 H4K16ac，这与 NSL 在上游作用于 MLL/SET 以调节某些启动子处的 H3K4me2 的观点一致，表明 NSL 和 MLL/SET 复合物之间的协调参与了某些基因的转录调控。总之，我们的结果表明细胞内 NSL 和 MLL/SET 复合物之间存在串扰。
